|Ph.D Student||Cohen-Segev Ravit|
|Subject||The Roles of the Small GTPase RhoJ in Cardiac Hypertrophy|
|Department||Department of Medicine||Supervisor||ASSOCIATE PROF. Izhak Kehat|
Abnormal cardiac enlargement and wall thickening is the heart’s adaptive response to various hypertrophic stimuli. Numerous transduction signaling cascades are involved in cardiac hypertrophy, however, there is still much to learn about the pro and anti-hypertrophic effectors involved. RhoJ, an endothelial-enriched small GTPase closely related to Cdc42, has key roles in regulating endothelial cell migration, wound healing, tube formation, and angiogenesis. To date, RhoJ has been studied mainly in cancer research and has been associated with progression of tumor growth and metastasis.
Here we aimed to discover the role of RhoJ in cardiac hypertrophy under pressure over-load and quiescent conditions, and understand whether RhoJ acts directly or indirectly in cardiomyocytes in the heart. To this purpose we used isolated neonatal rat ventricular myocytes system and mice models with gain and loss of function of RhoJ. While overexpression of RhoJ wildtype and constitutive active forms reduced cardiac hypertrophy in phenylephrine-treated cardiomyocytes, overexpression of dominant negative RhoJ exerted an opposite effect. However, mice with global knockout or cardiomyocyte specific overexpression of RhoJ displayed similar hypertrophic dimensions as compared with their controls. We conclude that RhoJ may have anti-hypertrophic qualities in isolated myocytes, however, the effects are diminished in whole mice models perhaps due to protein redundancy.
To study the effects of RhoJ on pulmonary fibrosis, knockout mice were intratracheally instilled with low and high dose of Bleomycin. Mice in the high dose-treated group were sacrificed after 5 days (acute injury) and their lungs were taken for histology. Knockout mice had a mild reduction in body weight as compared with wildtype mice and fewer inflammatory and fibrotic lesions in the lung. Mice in the low dose-treated group presented a 3-fold decrease in mortality rate as compared with their wildtype controls over the course of 3 weeks. Therefore we conclude that RhoJ may exert deleterious effects in pulmonary fibrosis. Additional studies are required for understanding the pathways involved.